Waste Clearance in the Brain and Neuroinflammation: A Novel Perspective on Biomarker and Drug Target Discovery in Alzheimer's Disease

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 5; p. 919
• Main Author: Uchida, Kazuhiko
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 07.03.2022; MDPI
• Subjects: Age; Aging; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Apoptosis; Aquaporins; Aβ clearance; Biomarkers; Biomarkers - cerebrospinal fluid; Blood-brain barrier; Brain - metabolism; Brain research; Caspase-1; Cell death; Cerebrospinal fluid; Clinical trials; Cognitive ability; Dementia; Dementia disorders; Etiology; glymphatic system; Homeostasis; Humans; Infections; Inflammasomes; Inflammation; innate immunity; mild cognitive impairment; Neurodegenerative diseases; Neuroinflammatory Diseases; Neuronal-glial interactions; Neurotoxicity; Pathogenesis; Pathogens; Production increases; Proteins; Review; Tau protein; Therapeutic targets; blood-brain barrier; mild cognitive impairment; innate immunity; glymphatic system; Aβ clearance
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11050919

Alzheimer's disease (AD) is a multifactorial disease with a heterogeneous etiology. The pathology of Alzheimer's disease is characterized by amyloid-beta and hyperphosphorylated tau, which are necessary for disease progression. Many clinical trials on disease-modifying drugs for AD have failed to indicate their clinical benefits. Recent advances in fundamental research have indicated that neuroinflammation plays an important pathological role in AD. Damage- and pathogen-associated molecular patterns in the brain induce neuroinflammation and inflammasome activation, causing caspase-1-dependent glial and neuronal cell death. These waste products in the brain are eliminated by the glymphatic system via perivascular spaces, the blood-brain barrier, and the blood-cerebrospinal fluid barrier. Age-related vascular dysfunction is associated with an impairment of clearance and barrier functions, leading to neuroinflammation. The proteins involved in waste clearance in the brain and peripheral circulation may be potential biomarkers and drug targets in the early stages of cognitive impairment. This short review focuses on waste clearance dysfunction in AD pathobiology and discusses the improvement of waste clearance as an early intervention in prodromal AD and preclinical stages of dementia.